Highly Efficient Olefin-Metathesis Catalysts - Pharmaceutical Technology

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Highly Efficient Olefin-Metathesis Catalysts
The authors describe the Piers' catalysts and detail latest progress in olefin-metathesis catalyst technology.


Pharmaceutical Technology



Figure 8 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
Results from Piers' work are shown in Figure 7 (6). Using 1 mol% catalyst and dichloromethane as the solvent, the reaction reached > 90% conversion within 2 h with Catalyst 2a while it took 4 h for the reaction to reach the same conversion with Catalysts 1a as well as with Schrock's catalyst (see Catalyst 8, Figure 8) (8). As shown in Figure 7, Grubbs Catalyst 4 and Grubbs fast-initiation Catalyst 9, which incorporate more labile 3-bromopyridine ligands, offer much lower conversion under otherwise identical conditions. Piers' catalysts possessing other noncoordinating counteranions (i.e., Catalysts 2b, 2c, 2d) display similar efficiencies under the same conditions (6, 7).


Table I
The use of Catalyst 2a for RCM of other substrates was further explored at room temperature by the Piers' group (6). Toluene was used as the solvent and the results from their publication are shown in Table I. These results indicate that Catalyst 2a is highly efficient for the RCM of a range of substrates at room temperature. For the formation of di- and trisubstituted 5-membered and 6-membered cycloalkenes (see Entries 1, 3, 4, Table I), the reaction went to completion in less than 10 min using 1 mol% catalyst loading. Disubstituted cyclopentene can be efficiently synthesized at lower catalyst loading (0.1 mol%, see Entry 2, Table I). For the formation of the more hindered trisubstituted cyclohexene (see Entry 5, Table I), the reaction went to completion within 1 h with 1 mol% catalyst loading. A higher catalyst loading (5 mol%) was used to drive the reaction to a high conversion for the formation of challenging 7-membered cycloalkene (see Entry 6, Table I), with the reaction reaching 85% conversion in less than 10 min.


Figure 9 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
Building upon Piers' initial results, the authors explored the use of the Piers' Catalyst 2b for the RCM of heteroatom containing substrates. N -Boc-diallyamine was selected as the model substrate, and RCM experiments were conducted at 30 C and 50 C with the use of only 0.05 mol% catalyst loading (see Reaction 4). Multiple solvents were screened. Toluene and methyl t -butyl ether (MTBE) were found to be the best for this reaction ( N -Boc-diallyamine concentration was 1M, and reaction time was 8 h). The results for Catalyst 2b are compared with the standard olefin-metathesis catalysts (see Catalysts 4 and 5, Figure 9).

Catalyst 2b gave complete conversion in both toluene and MTBE at 30 C, while ~90% conversions were produced at 50 C in both solvents. Catalyst 5 reached complete conversion at 50 C in toluene, but ~90% conversion under the other reaction conditions. Catalyst 4 performed poorly under these conditions, yielding < 50% conversion under all conditions tested.

Catalyst 2b was efficient at 30 C due to its fast initiation and stability at this temperature. The lower yields at 50 C are presumably due to catalyst degradation. Catalyst 5 performed well at 50 C in toluene but was less efficient in MTBE and in both solvents at 30 C. The poor performance of Catalyst 4 was attributed to its slow initiation under these conditions.


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